A Review of Select Centralized Pain Syndromes: Relationship With Childhood Sexual Abuse, Opiate Prescribing, and Treatment Implications for the Primary Care Physician.

Central sensitization is characterized by alterations in CNS processing. More specifically, the responsiveness of central neurons to input from unimodal and polymodal receptors is augmented, resulting in a pathophysiological state corresponding to CS, characterized by generalized or widespread hypersensitivity. Central sensitization encompasses impaired functioning of brain-orchestrated descending antinociceptive (inhibitory) mechanisms (especially, noradrenergic) and overactivation of ascending pain facilitatory pathways (especially, glutamatergic). The net result is augmentation rather than inhibition of nociceptive transmission. In addition to the switch in balance between inhibitory and facilitory pathways, CS entails altered sensory processing in the brain. Indeed, a modulated “pain signature” arises in the brain of patients with CS. The altered pain neuromatrix comprises of (1) increased activity in brain areas known to be involved in acute pain sensations, for example, the insula, anterior cingulate cortex, and the prefrontal cortex but not in the primary or secondary somatosensory cortex and (b) brain activity in regions generally not involved in acute pain sensations, for example, various brain stem nuclei, dorsolateral frontal cortex, and parietal associated cortex. 84 Although speculative, CS is believed to contribute to the pathogenesis of chronic pain in many FSS, including the ones previously discussed. 85

Fibromyalgia syndrome (FMS) is classified as a rheumatological disease with an estimated prevalence of 2% of the US population. 23 , 74 , 75 Patients with fibromyalgia commonly have lifelong histories of diffuse, chronic pain that is likely associated with other symptoms like headaches, dysmenorrhea, chronic fatigue, IBS and other FGID, painful bladder syndrome, endometriosis, and other regional pain syndromes. 4 In clinical practice, fibromyalgia should be suspected in patients having multifocal pain not fully explained by injury or inflammation and in most cases, musculoskeletal pain is the most prominent feature. Early diagnostic criteria for FMS was defined by the American College of Rheumatology (ACR) to include a history of widespread pain present greater than 3 months and excessive tenderness to digital palpation in at least 11 of the 18 muscle-tendon points. The 2010 ACR modifications on diagnostic criteria proposed that severity of FMS can be assessed using symptom severity (SS), a composite score that integrated physician-rated cognitive problems: unrefreshed sleep, fatigue, and a somatic symptoms count. Using SS and widespread pain index or tender point count, investigators recommended a new case definition of fibromyalgia, which still accounts for 88.7% of those who met the previous ACR definition. Apart from sorting through the differential diagnosis, laboratory testing is not useful for establishing a diagnosis of fibromyalgia. Basic laboratory evaluation may include complete blood count, routine serum chemistries, thyrotropin, vitamin D, erythrocyte sedimentation rate, and C-reactive protein. Serologic studies such as antinuclear antibody and rheumatoid factor assays are generally avoided unless symptoms or signs (eg, swollen joints) suggest an autoimmune disorder. 76 The etiology of fibromyalgia is unknown. Patients with FMS commonly perceive this illness to be disabling 77 and are more likely to incur chronic health problems such as metabolic syndrome. 78 It has been theorized that pain perceived in patients with FMS involves a state of “centralized” pain. Centralized refers to CNS origins of or amplification of pain, which does not imply that peripheral nociceptive input (ie, damage or inflammation of body regions) is not contributing to these individuals’ pain but rather they report hyperalgesia and allodynia. 79 In a similar regard, it can be thought that patients with fibromyalgia have impaired endogenous analgesic systems, in particular suboptimal functioning descending inhibitory pathways, which normally function to ameliorate pain. These pathways are both serotonergic (eg, dorsolateral pontine tegmentum) and noradrenergic (eg, rostral ventral medulla), which synapse in the spinal cord dorsal horn. 80 Although the link between central pain and abuse history is yet to be fully elucidated, this pain-prone phenotype predicts failure to respond to opioids or operations performed to reduce pain. 79 There appears to be an association between sexual abuse history and fibromyalgia as demonstrated by several systematic reviews and meta-analyses with statistically significant odds ratios. 14 , 24 , 81 The link between abuse history and fibromyalgia has proposed by some to involve dysregulation of the hypothalamic pituitary axis. However such a theory does not further explain the cause of pain nor associated symptoms among patients with fibromyalgia. 24 , 81 Perceived symptoms severity is worse in patients who are sexually abused when compared to those without such history among patients with fibromyalgia. In 1 study, when using cluster analysis to organize subsets of patients with FMS into more homogenous groups, the childhood maltreatment (ie, history of CSA and/or neglect) group was more likely to have higher perceived stress, the most subjective pain and the poorest measurement in global functioning. 74 Given their reduced global function, this subset of patients with FMS are more likely to incur frequent office visits and prolonged hospitalizations. Hence, eliciting a sexual abuse history should be an early step in evaluation of patients with fibromyalgia to foster better treatment outcomes. See Table 1 for a list of evidence-based treatment in FMS. There are very few studies that compare treatment outcomes in patients with FMS having sexual abuse history. Collectively, patients with FMS having underlying CSA have shown poor response to exclusive pharmacological interventions. One study showed CSA history to be a predictor of treatment response to brief interdisciplinary treatments consisting of education, self-management session, and cognitive behavioral therapy. 82 Although comorbid mood disorders could possibly mitigate the above-mentioned finding, a study that compared patients with CSA in adult patients with FMS to population controls, after adjusting for depressed mood, found that the differences was not accounted for by depression. In this same study, adjusting for depression, however, fully accounted for group difference in physical abuse and emotional neglect. 83

Chronic pain syndromes are often managed with opioid therapy, despite multiple studies and meta-analyses indicating that opioid therapy has limited efficacy in addressing chronic pain. 86 It has been estimated that 20% to 24% of chronic pain patients abuse opioids. 87 As such multiple screening tools such as the Opioid Risk Tool (and others) have been developed to assess a patient’s risk of developing an adverse drug-related behavior or an addiction to opioids. 88 There are multiple risk factors that have been found to increase one’s chance of becoming an opioid abuser, including a history of sexual abuse; as such, questions about sexual abuse can be found in the above-mentioned listed screening tools for potential opioid abuse. 89 Studies have demonstrated that those patients with a history of CSA report more FSS/chronic pain and greater utilization of some aspects of health care particularly related to pain issues, compared to controls of similar age and sex. 6 Furthermore, women who experienced CSA have a greater intensity of FSS symptoms and higher total number of symptoms. 90 Finally, in addition to more frequent visits/year to their primary care physician, women with a history of CSA reported more surgical procedures than nonabused women. 6 There is a paucity of data about trauma history among individuals dependent on prescription opioids. A 2013 study showed that more than one-third of individuals dependent on prescription opioids had sexual trauma. That same study reported CSA occurring at the (mean) age of 9.5 years. 91 See Figure 1 for a summary of the relationship between these variables. Relationship between centralized pain syndromes, childhood sexual abuse, and opiate usage. 14 , 88 , 91 , 92

Building greater awareness of the association between sexual abuse and somatic disorders may lead to improved health care delivery and outcomes for sexual abuse survivors. As a group, survivors of abuse have higher medical care use and incur greater costs compared with the general patient population. Analysis of expenditures demonstrates that costs are primarily the result of increased use of primary care, specialty medicine, and pharmacy and laboratory services. Higher medical use may also expose these patients to greater risk without clearly defined benefits, including increased abdominal and pelvic surgeries, adverse effects of medications, and chronic opioid use and dependence. 14 Despite evidence of high health care use among sexual abuse survivors, physicians remain largely unaware of this aspect of their patients' medical history. Only 5% of sexual abuse survivors report a history of abuse to their physician. However, heightened awareness of these specific health associations may prompt earlier recognition and improve care for sexual abuse survivors. 14 Given evidence of sexual abuse prevalence and related physical and mental health sequelae, we urge physicians to more routinely conduct inquiries about sexual abuse in patients with the identified somatic syndromes. Disclosure of abuse in the clinic setting may allow for earlier consultation with mental health professionals. Prompt recognition of the physical and psychological sequelae of sexual abuse may halt unnecessary medical escalation and provide care better suited to promote recovery. 14

Despite the above-mentioned review supporting a relationship between CSA resulting in adverse health consequences, the available data are far from decisive. In review of the existing research literature on CPS and CSA, some pervasive shortcomings emerged. First, in general, most research is limited to small, convenience samples, with insufficient attention to the design of control groups and to sample size. Second, both childhood and adult sexual abuse tend to be based on self-report, rather than by objective, externally corroborated evidence. It cannot be assumed that a retrospective account of interpersonal abuse accurately describes what transpired. Memory is an active and complex, highly individualistic process, intimately entwined with a person’s self-image (which are themselves determined not only by adverse life experiences but also by constitutional characteristics such as cognitive style and coping strategies). One study demonstrated discrepant results in regard to the relationship between history of sexual abuse and chronic pain, depending on whether sexual abuse was assessed by retrospective recall or from official records. 93

Given the high prevalence of sexual abuse and the association of abuse with poor health status, it is important to ask the question Do physicians and other health professionals know about their patients' abuse history? A national survey of women found that although about 30% experienced child sexual, physical, or emotional abuse, only 21% of the abused said they had discussed these issues with a physician. In another study of a primary care clinic, although the prevalence of childhood (37%) and adult (29%) sexual abuse was high and most women felt it was appropriate for their physician to inquire about previous abuse (61%), only 4% indicated that their health care provider asked about such incidents. 3 Why and when should health practitioners ask about abuse? Inquiring about abuse makes sense when the clinical data are suggestive of abuse. For example, it makes sense when (1) the patient has numerous painful chronic health symptoms (eg, gastrointestinal, gynecologic, headache, widespread pain, and LBP) and (2) the patient is significantly affected by these symptoms, that is, frequent office visits/surgical intervention, poor quality of life, and severe disability. If the primary care provider is contemplating opiate maintenance therapy for any of these painful chronic conditions, past history of CSA significantly increases the probability of opiate misuse and as the rates of fatal overdose have increased concomitantly with an increase in the number of patients on long-term opioid therapy. 25 Although the following describes classes of medications and their level of evidence in treating FMS, in general, medications with the highest level of evidence in fibromyalgia are also being shown to work in subsets of individuals with CPS. Strong evidence has been demonstrated for dual reuptake inhibitors, such as the tricyclic compounds amitriptyline and cyclobenzaprine, and the serotonin norepinephrine reuptake inhibitors (norepinephrine serotonin reuptake inhibitors), milnaciprin and duloxetine, and for the anticonvulsants pregabalin and gabapentin. Modest evidence exists for tramadol and selective serotonin reuptake inhibitors, with weak evidence for S -adenosyl- l -methionine. 4 Classes of drugs that are quite effective for “peripheral” pain due to damage or inflammation in peripheral tissues such as nonsteroidal anti-inflammatory drugs and opioids are either less or not effective analgesics in CPS. There are even some data suggesting that giving opioids to individuals with CPS may worsen their pain, by leading to opioid-induced hyperalgesia that could augment and worsen the baseline hyperalgesia. 4 Finally, although the aforementioned pharmacological therapies may work across all or most of these conditions, nonpharmacological therapies such as education, exercise, and cognitive behavioral therapy have been demonstrated to be effective across nearly all of the CPS conditions, as well. 4